ABSTRACT Low back pain is the most common musculoskeletal disease and a major cause of disability. This costly condition affects bone and soft tissues of the spine and the principal underlying cause is degeneration of the intervertebral disc (IVD). Aging is a main risk factor for IVD degeneration (IDD). Age-related changes in the IVD cells and extracellular matrix are thought to compromise tissue homeostasis and trigger the onset of IDD. However, the precise molecular mechanisms underlying IDD are not well understood. The Forkhead box O (FoxO) transcription factors are evolutionarily conserved genes implicated in longevity and cellular homeostasis. Dysregulated FoxO expression and activity has been linked to several age-related diseases.. We have reported that FoxO proteins support resistance to oxidative stress and promote autophagy in human articular chondrocytes, and that FoxO expression is reduced in articular cartilage during aging and osteoarthritis. Our preliminary studies show that FoxO expression is reduced in IVD and endplates of aged mice and that in mice with col2a1cre-driven deletion of FoxO manifest abnormal organization and hypertrophy of the IVD and the cartilaginous endplates. These observations support hypothesis is that FoxO are important factors controlling IVD homeostasis and that a reduction of FoxO expression in IVD is an early event that eventually leads to IVD degeneration. In Aim 1 we will measure the expression of FoxO in human and mouse IVD throughout a broad aging spectrum and different degrees of degeneration, and we will correlate changes in FoxO expression with histopathological changes in IVD and with known mediators of IDD. In Aim 2 we will examine the role of FoxO in spine in vivo by analyzing spontaneous histological and molecular changes in the IVD of aggrecan-CreERT2 -FoxOfl/fl mice with postnatal, tissue-specific deletion of FoxO. The proposed project will establish proof of principle that aging-related reduction in FoxO expression is an early and critical event in IDD pathogenesis. This will provide the foundation for therapeutic approaches aimed at modulating FoxO expression and/or activity to prevent age-related and injury-induced IVD degeneration.